Role of Thymidylate Synthase Gene Variations in Colorectal Cancer Patients

  • Georg Lurje
  • Heinz-Josef Lenz
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)


Colorectal cancer (CRC) is the third most common cause of cancer-related death in women and men in the United States. The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based chemotherapy regimens with the addition of irinotecan (CPT-11) or oxaliplatin. It still remains a challenge for oncologists to evaluate the reasons for a wide variation in response and toxicity among patients undergoing systemic 5-FU based chemotherapy. Pharmacogenomics has emerged as a useful tool to address the variations by evaluating the interplay between genotype and drug efficacy. Identifying a reliable panel of prognostic and predictive markers is critical in selecting an individualized chemotherapy regimen based on a particular tumor genotype.

A substantial body of evidence has been accumulated in recent years, demonstrating that the level of thymidylate synthase (TS) mRNA and protein expression significantly correlates with sensitivity and resistance to TS-targeted 5-FU based chemotherapy regimens. However, the cause of the variability in TS expression still remains unclear, even though several molecular mechanisms have been identified that seem to regulate the expression of TS, which may have an impact on the response to 5-FU based chemotherapy.

TS gene expression is associated with the presence of polymorphic tandem repeats (double or triple) in the 5′-UTR region (thymidylate synthase enhancer region, TSER) of the TS gene (1,2). Patients with colon cancer who are homozygous for the triple tandem repeat (TSER-3R/3R) had significantly higher levels of intratumoral TS compared with those with double tandem repeats (3). Furthermore, Mandola et al. identified a G to C single nucleotide polymorphism (SNP) within the second repeat of the 5′-UTR TSER, which may be responsible for the transcriptional up-regulation of TS. A third polymorphic change has been reported in the 3′UTR region of TS at position 1494, a 6 bp repeat.

These three different polymorphisms in the same gene obviously complicate efforts aimed at understanding the effects of each individual polymorphism. TS expression levels, tumor response, and toxicity are functions of multiple TS gene alterations, rather than the result of one single polymorphism. This review will provide an update of the most recent data on 5-FU metabolism and TS gene variations in CRC.

Key Words

Thymidylate synthase pharmacogenomics polymorphism chemo-therapy TSER SNP TS 1494–6 bp/–6 bp 


  1. 1.
    Horie N, Aiba H, Oguro K et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995;20:191–197.CrossRefPubMedGoogle Scholar
  2. 2.
    Marsh S, McLeod HL. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer 2001;1:175–178; discussion 179–181.CrossRefPubMedGoogle Scholar
  3. 3.
    Pullarkat ST, Stoehlmacher J, Ghaderi V et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001;1:65–70.PubMedGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–130.CrossRefPubMedGoogle Scholar
  5. 5.
    de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.PubMedGoogle Scholar
  6. 6.
    Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041–1047.CrossRefPubMedGoogle Scholar
  7. 7.
    Grothey A, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–1214.CrossRefPubMedGoogle Scholar
  8. 8.
    Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–237.CrossRefPubMedGoogle Scholar
  9. 9.
    Giantonio BJ, Levy DE, O’Dwyer et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 2006;17:1399–1403.CrossRefPubMedGoogle Scholar
  10. 10.
    Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.CrossRefPubMedGoogle Scholar
  11. 11.
    McLeod HL, Papageorgio C, Watters JW. Using genetic variation to optimize cancer chemotherapy. Clin Adv Hematol Oncol 2003;1:107–111.PubMedGoogle Scholar
  12. 12.
    McLeod HL, Yu J. Cancer pharmacogenomics: SNPs, chips, and the individual patient. Cancer Invest 2003;21:630–640.CrossRefPubMedGoogle Scholar
  13. 13.
    Ichikawa W, Uetake H, Shirota Y et al. Combination of dihydropyrimidine dehydrogenase and thymidylate synthase gene expressions in primary tumors as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Clin Cancer Res 2003;9: 786–791.PubMedGoogle Scholar
  14. 14.
    Salonga D, Danenberg KD, Johnson M et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000;6:1322–1327.PubMedGoogle Scholar
  15. 15.
    Heidelberger C, Chaudhuri NK, Danneberg P et al. Fluorinated pyrimidines: a new class of tumour-inhibitory compounds. Nature 1957;179:663–666.CrossRefPubMedGoogle Scholar
  16. 16.
    Danenberg PV. Thymidylate synthetase: a target enzyme in cancer chemotherapy. Biochim Biophys Acta 1977;473:73–92.PubMedGoogle Scholar
  17. 17.
    Danenberg PV. Pharmacogenomics of thymidylate synthase in cancer treatment. Front Biosci 2004;9:2484–2494.CrossRefPubMedGoogle Scholar
  18. 18.
    Aschele C, Sobrero A, Faderan MA et al. Novel mechanism(s) of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 1992;52:1855–1864.PubMedGoogle Scholar
  19. 19.
    Cohen V, Panet-Raymond V, Sabbaghian N et al. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003;9:1611–1615.PubMedGoogle Scholar
  20. 20.
    Thirion P, Michiels S, Pignon JP et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004;22:3766–3775.CrossRefPubMedGoogle Scholar
  21. 21.
    Mathijssen RH, van Alphen RJ, Verweij J et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001;7:2182–2194.PubMedGoogle Scholar
  22. 22.
    Simpson D, Dunn C, Curran M et al. Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer. Drugs 2003;63:2127–2156.CrossRefPubMedGoogle Scholar
  23. 23.
    Venook A. Critical evaluation of current treatments in metastatic colorectal cancer. Oncologist 2005;10:250–261.CrossRefPubMedGoogle Scholar
  24. 24.
    Hoshino S, Yamashita Y, Maekawa T et al. Effects on DNA and RNA after the administration of two different schedules of 5-fluorouracil in colorectal cancer patients. Cancer Chemother Pharmacol 2005;56:648–652.CrossRefPubMedGoogle Scholar
  25. 25.
    Kubota T, Watanabe M, Otani Y et al. Different pathways of 5-fluorouracil metabolism after continuous venous or bolus injection in patients with colon carcinoma: possible predictive value of thymidylate synthetase mRNA and ribonucleotide reductase for 5-fluorouracil sensitivity. Anticancer Res 2002;22:3537–3540.PubMedGoogle Scholar
  26. 26.
    O'Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–507.CrossRefPubMedGoogle Scholar
  27. 27.
    Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer: a tale of two drugs: implications for biochemical modulation. J Clin Oncol 1997;15:368–381.PubMedGoogle Scholar
  28. 28.
    Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol 1998;16:301–308.Google Scholar
  29. 29.
    Schuller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297.CrossRefPubMedGoogle Scholar
  30. 30.
    Van Cutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001;19:4097–4106.PubMedGoogle Scholar
  31. 31.
    El Sayed YM, Sadee W. Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes. Cancer Res 1983;43:4039–4044.PubMedGoogle Scholar
  32. 32.
    Tuchman M, Ramnaraine ML, O'Dea RF. Effects of uridine and thymidine on the degradation of 5-fluorouracil, uracil, and thymine by rat liver dihydropyrimidine dehydrogenase. Cancer Res 1985;45:5553–5556.PubMedGoogle Scholar
  33. 33.
    Tatsumi K, Fukushima M, Shirasaka T et al. Inhibitory effects of pyrimidine, barbituric acid, and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res 1987;78: 748–755.PubMedGoogle Scholar
  34. 34.
    Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its anti-tumor activity in rats. Cancer Res 1993;53:4004–4009.PubMedGoogle Scholar
  35. 35.
    Takechi T, Nakano K, Uchida J et al. Anti-tumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 1997;39:205–211.CrossRefPubMedGoogle Scholar
  36. 36.
    van Groeningen CJ, Peters GJ, Schornagel JH et al. Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol 2000;18:2772–2779.PubMedGoogle Scholar
  37. 37.
    Chollet P, Schoffski P, Weigang-Kohler K et al. Phase II trial with S-1 in chemotherapy-naive patients with gastric cancer: a trial performed by the EORTC Early Clinical Studies Group (ECSG). Eur J Cancer 2003;39:1264–1270.CrossRefPubMedGoogle Scholar
  38. 38.
    Koizumi W, Kurihara M, Nakano S et al. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. for the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000;58:191–197.CrossRefPubMedGoogle Scholar
  39. 39.
    Sakata Y, Ohtsu A, Horikoshi N et al. Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 1998;34:1715–1720.CrossRefPubMedGoogle Scholar
  40. 40.
    Koizumi W, Tanabe S, Saigenji K et al. Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer 2003;89:2207–2212.CrossRefPubMedGoogle Scholar
  41. 41.
    Ajani JA, Faust J, Ikeda K et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma.J Clin Oncol 2005;23:6957–6965.CrossRefPubMedGoogle Scholar
  42. 42.
    Mandola MV, Stoehlmacher J, Muller-Weeks S et al. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003;63:2898–2904.PubMedGoogle Scholar
  43. 43.
    Berger SH, Jenh CH, Johnson LF et al. Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol 1985;28:461–467.PubMedGoogle Scholar
  44. 44.
    Kundu NG, Heidelberger C. Cyclopenta(f)isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 3. Interaction of 6-carbamylmethyl-8-methyl-7 H-cyclopenta(f)- isoquinolin-3(2 H)-one with deoxyribonucleic acids and polydeoxyribonucleotides. Biochem Biophys Res Commun 1974;60:561–568.CrossRefPubMedGoogle Scholar
  45. 45.
    Shirota Y, Stoehlmacher J, Brabender J et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001;19:4298–4304.PubMedGoogle Scholar
  46. 46.
    Stoehlmacher J, Park DJ, Zhang W et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 2004;91:344–354.PubMedGoogle Scholar
  47. 47.
    Leichman L, Lenz HJ, Leichman CG et al. Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: preliminary report from an ongoing trial. Eur J Cancer 1995;31A: 1306–1310.Google Scholar
  48. 48.
    Villafranca E, Okruzhnov Y, Dominguez MA et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001;19:1779–1786.PubMedGoogle Scholar
  49. 49.
    Iacopetta B, Grieu F, Joseph D et al. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 2001;85:827–830.CrossRefPubMedGoogle Scholar
  50. 50.
    Carlini LE, Meropol NJ, Bever J et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 2005;11:1226–1236.PubMedGoogle Scholar
  51. 51.
    Gibson TB. Polymorphisms in the thymidylate synthase gene predict response to 5-fluorouracil therapy in colorectal cancer. Clin Colorectal Cancer 2006;5:321–323.PubMedGoogle Scholar
  52. 52.
    Kralovanszky J, Koves I, Orosz Z et al. Prognostic significance of the thymidylate biosynthetic enzymes in human colorectal tumors. Oncology 2002;62:167–174.CrossRefPubMedGoogle Scholar
  53. 53.
    Nakagawa T, Tanaka F, Otake Y et al. Prognostic value of thymidylate synthase expression in patients with p-stage I adenocarcinoma of the lung. Lung Cancer 2002;35:165–170.CrossRefPubMedGoogle Scholar
  54. 54.
    Marsh S. Thymidylate synthase pharmacogenetics. Invest New Drugs 2005;23:533–537.CrossRefPubMedGoogle Scholar
  55. 55.
    Marsh S, Collie-Duguid ES, Li T et al. Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics 1999;58:310–312.CrossRefPubMedGoogle Scholar
  56. 56.
    Kawakami SD, Omura K, Park J et al. Effects of polymorphic tandem repeat sequence on the in vitro translation of messenger RNA. Proc Am Assoc Cancer Res (Abstract) 1999;40::436–437.Google Scholar
  57. 57.
    Kawakami K, Omura K, Kanehira E et al. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999;19:3249–3252.PubMedGoogle Scholar
  58. 58.
    Etienne MC, Chazal M, Laurent-Puig P et al. Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses. J Clin Oncol 2002;20:2832–2843.CrossRefPubMedGoogle Scholar
  59. 59.
    Mandola MV, Stoehlmacher J, Zhang W et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004;14:319–327.CrossRefPubMedGoogle Scholar
  60. 60.
    Kawakami K, Watanabe G. Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 2003;63:6004–6007.PubMedGoogle Scholar
  61. 61.
    Ulrich CM, Bigler J, Velicer CM et al. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000;9:1381‑1385.PubMedGoogle Scholar
  62. 62.
    Lenz H-J, Zhang W, Zahedy S et al. A 6 base-pair deletion in the 3 UTR of the thymidylate synthase (TS) gene predicts TS mRNA expression in colorectal tumors: a possible candidate gene for colorectal cancer risk. Proc Am Assoc Cancer Res (Abstract) 2002;43.Google Scholar
  63. 63.
    Dotor E, Cuatrecases M, Martinez-Iniesta M et al. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 2006;24:1603–1611.CrossRefPubMedGoogle Scholar
  64. 64.
    Vogelstein B, Fearon ER, Kern SE et al. Allelotype of colorectal carcinomas. Science 1989;244: 207–211.CrossRefPubMedGoogle Scholar
  65. 65.
    Zinzindohoue F, Ferraz JM, Laurent-Puig P. Thymidylate synthase promoter polymorphism. J Clin Oncol 2001;19:3442.PubMedGoogle Scholar
  66. 66.
    Uchida K, Hayashi K, Kawakami K et al. Loss of heterozygosity at the thymidylate synthase (TS) locus on chromosome 18 affects tumor response and survival in individuals heterozygous for a 28-bp polymorphism in the TS gene. Clin Cancer Res 2004;10:433–439.CrossRefPubMedGoogle Scholar
  67. 67.
    Morganti M, Ciantelli M, Giglioni B et al. Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers. Eur J Cancer 2005;41:2176–2183.CrossRefPubMedGoogle Scholar
  68. 68.
    Jakobsen A, Nielsen JN, Gyldenkerne N et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 2005;23:1365–1369.CrossRefPubMedGoogle Scholar
  69. 69.
    Hitre E, Budai B, Adleff V et al. Influence of thymidylate synthase gene polymorphisms on the survival of colorectal cancer patients receiving adjuvant 5-fluorouracil. Pharmacogenet Genomics 2005;15:723–730.CrossRefPubMedGoogle Scholar
  70. 70.
    Marcuello E, Altes A, del Rio E et al. Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 2004;112:733–737.CrossRefPubMedGoogle Scholar
  71. 71.
    Kawakami K, Graziano F, Watanabe G et al. Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res 2005;11:3778–3783.CrossRefPubMedGoogle Scholar
  72. 72.
    Tan RM, Zehnbauer B, Picus J et al. TYMS genotype polymorphism directed neoadjuvant chemoradiation for patients (pts) with T3/T4 adenocarcinoma of the rectum (Abstract). 2006 Gastrointestinal Cancers Symposium 2006.Google Scholar
  73. 73.
    Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004;22:529–536.CrossRefPubMedGoogle Scholar
  74. 74.
    Heggie GD, Sommadossi JP, Cross DS et al. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 1987;47:2203–2206.PubMedGoogle Scholar
  75. 75.
    Van Kuilenburg AB, Vreken P, Abeling NG et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 1999;104:1–9.CrossRefPubMedGoogle Scholar
  76. 76.
    van Kuilenburg AB, Muller EW, Haasjes J et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1 G>A mutation causing DPD deficiency. Clin Cancer Res 2001;7:1149–1153.PubMedGoogle Scholar
  77. 77.
    van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 2004;40:939–950.CrossRefPubMedGoogle Scholar
  78. 78.
    Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest 1988;81:47–51.CrossRefPubMedGoogle Scholar
  79. 79.
    Isshi K, Sakuyama T, Gen T et al. Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU. Int J Clin Oncol 2002;7:335–342.CrossRefPubMedGoogle Scholar
  80. 80.
    Ichikawa W, Nihei Z, Uetake H et al. UFT plus leucovorin for metastatic colorectal cancer: Japanese experience. Oncology (Williston Park) 2000;14:41–43.Google Scholar
  81. 81.
    Alati T, Worzalla JF, Shih C et al. Augmentation of the therapeutic activity of lometrexol -(6-R)5,10-dideazatetrahydrofolate- by oral folic acid. Cancer Res 1996;56:2331–2335.PubMedGoogle Scholar
  82. 82.
    Morgan SL, Baggott JE, Vaughn WH et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9–18.CrossRefPubMedGoogle Scholar
  83. 83.
    Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001;98:231–234.CrossRefPubMedGoogle Scholar
  84. 84.
    Sohn KJ, Croxford R, Yates Z et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 2004;96:134–144.CrossRefPubMedGoogle Scholar
  85. 85.
    Engstrom P. Update: NCCN colon cancer Clinical Practice Guidelines. J Natl Compr Canc Netw 2005;3 Suppl 1:S25–28.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Georg Lurje
    • 1
  • Heinz-Josef Lenz
    • 1
  1. 1.Division of Medical OncologyUniversity of Southern California Norris Comprehensive Cancer Center Keck School of MedicineLos AngelesUSA

Personalised recommendations